Human gammadelta T cells: a nonredundant system in the immune-surveillance against cancer.

Down-regulation of expression of MHC alleles, as well as tumor-specific antigens, is observed frequently during tumor progression, resulting in an impairment of MHC-restricted, alphabeta-T-cell-mediated, tumor-specific immunity. Given the unique set of antigens recognized and the lack of requirement for classical antigen-presenting molecules, gammadelta T cells might, therefore, represent a nonredundant system in anticancer surveillance, as proposed for the immune response against pathogens. Evidence that gammadelta and alphabeta T cells make distinct contributions to anticancer surveillance has been provided recently in mice. Here, we discuss the potential role played by resident Vdelta1(+) and circulating Vdelta2(+) T cells in the defense against solid tumors and hematological malignancies.     

Effector and regulatory events during natural killer–dendritic cell interactions

Summary:  The different cell types of the innate immune system can interact with each other and influence the quality and strength of an immune response. The cross talk between natural killer (NK) cells and myeloid dendritic cells (DCs) leads to NK cell activation and DC maturation. Activated NK cells are capable of killing DCs that fail to undergo proper maturation ('DC editing'). Encounters between NK cells and DCs occur in both inflamed peripheral tissues and lymph nodes, where both cell types are recruited by chemokines released in the early phases of inflammatory responses. Different NK cell subsets (CD56^brightCD16⁻ versus CD56⁺CD16⁺) differ in their homing capabilities. In particular, CD56^brightCD16⁻ NK cells largely predominate the lymph nodes. In addition, these two subsets display major functional differences in their cytolytic activity, cytokine production, and ability to undergo proliferation. NK cell functions are also greatly influenced by the presence of polarizing cytokines such as interleukin (IL)-12 and IL-4. The cytokine microenvironment reflects the presence of different cell types that secrete such cytokines in response to microbial products acting on different Toll-like receptors (TLRs). Moreover, NK cells themselves can respond directly to microbial products by means of TLR3 and TLR9. Thus, it appears that the final outcome of a response to microbial infection may greatly vary as a result of the interactions occurring between different pathogen-derived products and different cell types of the innate immunity system. These interactions also determine the quality and strength of the subsequent adaptive responses. Remarkably, NK cells appear to play a key role in this complex network.     

IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors

The NK cell maturation from CD34(+) Lin(-) hematopoietic cell precursors is a complex process that requires the direct contact with stromal cells and/or the synergistic effect of different cytokines. In this study we show that IL-21 is capable of inducing an accelerated NK cell maturation when added to cultures of CD34(+) Lin(-) cells isolated from human cord blood supplemented with IL-15, Flt3-L and SCF. After 25 days of culture, 50% of CD56(+) cells expressed various NK cell markers including the NKp46 and NKp30 triggering receptors, the CD94/NKG2A inhibitory receptor and CD16. At day 35, substantial fractions of NK cells expressed KIR, CD8 and CD2, i.e. surface markers expressed by mature NK cells, that are virtually undetectable in developing NK cells cultured in the absence of IL-21. Remarkably, similar to mature NK cells all these markers were included in the CD56(dim) cell fraction, while the CD56(bright) population was only composed of CD94/NKG2A(-) and CD94/NKG2A(+) cells. Thus, IL-21 allows the induction of a full NK cell maturation in vitro and offers an important tool for dissecting the molecular mechanisms involved in different steps of NK cell maturation and in the acquisition of a mature KIR repertoire.     

Muscarinic modulation of acetylcholine release from slices of guinea pig nucleus basalis magnocellularis

Spontaneous and electrically evoked endogenous acetylcholine release and [³H]-choline efflux from slices of guinea pig nucleus basalis magnocellularis (nbM) were studied. Tetrodotoxin reduced the spontaneous endogenous release by 55%, while the Ca²⁺-free medium reduced it by about 30%. Evoked [³H]-choline efflux was Na⁺ and Ca²⁺ dependent and frequency related. Physostigmine, 30 μM, nearly halved the stimulation-evoked efflux; atropine, 0.15 μM, not only antagonized, but even reversed this effect into facilitation. Pirenzepine, 1 μM, and AFDX 116, 1 μM, were less effective than atropine, and reversed the inhibitory effect of physostigmine only when applied together. 4-DAMP, 0.01 μM, was ineffective. These findings indicate that acetylcholine release in guinea pig nbM slices is inhibited by the cooperation of muscarinic autoreceptors, possibly belonging to the M₁ and M₂ subclasses.     

TUBB3 E410K syndrome: Case report and review of the clinical spectrum of TUBB3 mutations

The tubulinopathies refer to a wide range of brain malformations caused by mutations in one of the seven genes encoding different tubulin's isotypes. The β‐tubulin isotype III (TUBB3) gene has a primary function in nervous system development and axon generation and maintenance, due to its neuron‐specific expression pattern. A recurrent heterozygous mutation, c.1228G > A; p.E410K, in TUBB3 gene is responsible of a rare disorder clinically characterized by congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual disability and a wide range of neurological and endocrine abnormalities. Other mutations have been described spanning the entire gene and genotype–phenotype correlations have been proposed. We report on a 3‐year‐old boy in whom clinical exome sequencing allowed to identify a de novo TUBB3 E410K mutation as the molecular cause underlying a complex phenotype characterized by a severe bilateral palpebral ptosis refractory to eye surgery, psychomotor delay, absent speech, hypogonadism, celiac disease, and cyclic vomiting. Brain MRI revealed thinning of the corpus callosum with no evidence of malformation cortical dysplasia. We reviewed available records of patients with TUBB3 E410K mutation and compared their phenotype with the clinical outcome of patients with other mutations in TUBB3 gene. The present study confirms that TUBB3 E410K results in a clinically recognizable phenotype, unassociated to the distinct cortical dysplasia caused by other mutations in the same gene. Early molecular characterization of TUBB3 E410K syndrome is critical for targeted genetic counseling and prompt prospective care in term of neurological, ophthalmological, endocrine, and gastrointestinal follow‐up.     

Is choledochoduodenostomy in the treatment of stones in the common bile duct an obsolete technique?

The complex pathogenesis of bile duct stones, the anatomical properties of the biliary tree, the patient's age, associated diseases, as well as the technical devices available, may explain the great variety of procedures and preferences of different groups in the treatment of choledocholithiasis. Since no technique is infallible or free of complications, it seems unfair to argue that procedures whose efficacy has been proven by many authors are obsolete. This is the case of choledochoduodenostomy (CDS) in the treatment of common bile duct (CBD) stones. The complications associated with CDS, (ascending cholangitis, and sump syndrome) have been overemphasized and have led CDS to be rejected by many surgeons. Our experience with this technique is good and concurs with that of Madden and others.Data on 125 patients with CBD stones treated with CDS between 1968 and 1982 are analyzed. Sixty-eight of them were female and the mean age was 61.4 years; 73.6% were more than 50 years old. There were frequent accompanying diseases, especially cardiovascular ones. More than half of the patients had a previous operation on the biliary tree. The duct diameter was always greater than 20 mm and it was frequently associated with stenosis of the distal choledochus. Floercken's technique of CDS was the most frequently used, after Kocher's maneuver had been performed. There was no intraoperative mortality. Postoperative mortality was 3.2% and is analyzed in detail. The incidence of postoperative complications was 42.4%. Most were septic complications or those ascribed to accompanying diseases. Late operative cholangitis was present in 1.6% of patients, comparable with reports of other authors. We encourage the use of CDS in the treatment of CBD stones provided that: (a) careful attention is paid to its clinical indications, considering that the patient may benefit from alternative techniques, for example, duodenoscopic papillotomy; and (b) choledochal dilatation is greater than 20 mm in diameter and the choledochal and duodenal walls are normal. We specifically recommend CDS as the primary operation for patients with choledochal funnel syndrome. The operation is simple, restores normal digestive function, and almost always resolves the problems of CBD stones in high-risk patients.

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Resumen La compleja patogenia de los cálculos del colédoco, las propiedades anatómicas del árbol biliar, la edad del paciente, las patologías asociadas y otros factores, junto con la disponibilidad de diversos elementos técnicos, explican la gran variedad de procedimientos y de preferencias por parte de los cirujanos en el tratamiento y de preferencias por parte de los cirujanos en el tratamiento de la litiasis biliar. Puesto que ninguna técnica operatoria es infalible ni totalmente libre de complicaciones, parece injusto argumentar que procedimientos cuya eficacia ha sido comprobada por muchos autores sean calificados como obsoletos. Tal es el caso de la coledocoduodenostomía (CDS) en el tratamiento de los cálculos del colédoco. Las complicaciones asociadas con la CDS (colangitis ascendente y el sindrome del segmento distal ciego) han sido exageradas, lo cual ha llevado a muchos cirujanos a rechazar la CDS. Nuestra experiencia con esta técnica es buena y está de acuerdo con la de Madden y de otros. Se analizaron los datos en 125 pacientes con cálculos del colédoco tratados con CDS entre 1968 y 1982. Sesenta y ocho eran mujeres y la edad promedio fué de 61.4 años; 73.6% eran mayores de cincuenta años. Otras enfermedades asociadas fueron halladas con frecuencia, especialmente las cardiovasculares. Más de la mitad de los pacientes tenían historia de una operación previa sobre el árbol biliar. El diámetro del colédoco fué superior a 20 mm en todos los casos y con frecuencia se encontró estenosis árbol de la porción distal. La técnica de Floercken fué la más frecuentemente utilizada, una vez realizada la maniobra de Kocher. No hubo mortalidad intraoperatoria. La mortalidad postoperatoria fué de 3.2% y se analiza en detalle. La tasa de complicaciones postoperatorias fué de 42.4%, incluyendo las sistematicas y las locales, leves y severas, habiéndose observado predominancia de las complicaciones sépticas y de aquellas relativas a patologiás asociadas. La colangitis operatoria tardía ocurrió en el 1.6% de los pacientes, tasa comparable a la informada por otros autores. Nosotros preconizamos el uso de la CDS en el tratamiento de los cálculos del colédoco siempre que: (a) se preste atención cuidadosa a sus indicaciones clínicas, considerando que el paciente puede beneficiarse con otras alternativas, por ejemplo la papilotomía duodenoscópica; y (b) la dilatación del colédoco sea de un diámetro superior a 20 mm y que las paredes tanto del colédoco como del duodeno sean normales. Específicamente recomendamos la CDS como la operación primaria para pacientes con el síndrome del embudo coledociano (estenosis distal con dilatación proximal). La operación es sencilla, restaura la función digestiva normal y en forma casi uniforme resuelve los problemas que producen los cálculos del colédoco en pacientes de alto riesgo.

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Résumé La pathogénie complexe de la lithiase biliaire, les caractères anatomiques des voies biliaires ainsi que l'âge des malades, les affections associées et la grande variété des méthodes techniques expliquent la grande diversité des procédés de traitement de la lithiase choledocienne employés par les différentes équipes chirurgicales. Aucune technique n'étant infaillible ou exempte de complications, il paraît inconsidéré d'abandonner toute méthode qui a fait ses preuves. Il en est ainsi de la choledocoduodénostomie. Les complications attribuées à ce type d'intervention comme l'angiocholite ascendante, et le syndrome du moignon sous-anastomotique ont été exagérées conduisant de nombreux chirurgiens à l'écarter de leur pratique. Notre expérience de la choledocoduodénostomie est bonne et coincide avec celle de Madden et d'autres auteurs. Les données recueillies chez 125 malades qui présentaient des calculs de la V.B.P. et qui furent traités par la choledocoduodénostomile de 1968 à 1982 ont été étudiées. Soixante-huit étaient des femmes. La moyenne d'âge était de 61.4 ans, 73.6% étaient âgés de plus de 50 ans. Les affections associées étaient fréquentes en particulier les affections cardiovasculaires. Plus de la moitié de nos opérés avaient déjà subi une intervention sur la voie biliaire. Le diamètre de la voie biliaire a toujours été supérieur à 20 mm et la dilatation se trouvait souvent au dessus d'un rétrécissement du bas cholédoque. La technique de Floercken fut le plus souvent employée après le décollement du bloc duodénopancréatique. Il n'y eu aucun décès peropératoire. La mortalité postopératoire s'est élevée à 3.2% et a été étudiée avec précision. Le taux des complications postopératoires a atteint 42.4%, dont les infections et les désordres secondaires aux affections associées occupent la première place. Le taux de l'angiocholite postopératoire tardive s'est élevé à 1.6%, identique à celui rapporté par d'autres auteurs. Notre expérience nous permet de recommander la choledocoduodénostomie à condition (a) d'apporter une attention particulière aux indications après avoir pris en considération la possibilité de traiter la lithiase par une autre méthode, la sphinctérotomie endoscopique par exemple; et (b) de la réserver aux cas où le diamètre de la V.B.P. est supérieur à 20 et ou les parois de la voie biliaire et du duodénum sont normales. Nous considérons qu'elle est particulièrement indiquée en présence du syndrome du cholédoque en entonnoir. L'intervention est simple, restaure la fonction digestive normale et résoud le problème des calculs de la V.B.P. chez les malades de haut risque.

     

High resolution real-time B-mode echotomography in the diagnosis of extracranial carotid lesions. Comparison with traditional angiography

Summary Tumour growth essentially requires fibrin formation and fibrinopeptide A (FPA) is liberated into the circulation on fibrin formation. In the present study, a possible elevation of serum FPA level was examined in patients with metastatic brain tumour. A significant elevation of serum FPA level was shown in all 6 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. It was extremely high in 2 patients with rapidly growing tumour. However, such a significant elevation was not shown in 3 cancer patients without brain metastasis or in 1 patient with a huge meningioma. This suggests the possibility that the presence of metastatic brain tumour could be detected by measuring FPA in blood drawn form the internal jugular vein. This also suggests the tendency that elevation of serum FPA is higher in patients with more rapidly growing tumour.Infusion of urokinase into the internal carotid artery resulted in an elevation of serum fibrinopeptide B (1)15–42 (FPB) in 5 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. This suggests that urokinase could induce fibrinolysis in the tumour tissue, though this remains in conclusive because of the lack of complete controls.     

Drop attack as the only symptom of type 1 Chiari malformation. Illustration by a case

An unusual case of Chiari type I malformation is presented. The only symptom was a "drop attack" during sneezing or coughing. The possible pathogenetic mechanisms are briefly reviewed and the good results of the surgical therapy are stressed.     

Polyphenols and Human Health: The Role of Bioavailability

Polyphenols are a group of phytochemicals with potential health-promoting effects. They are classified as flavonoid (flavonols, flavanols, flavones, flavanones, isoflavones, and anthocyanins) and non-flavonoid molecules (phenolic acids, hydroxycinnamic acids, lignans, stilbenes, and tannins). Although an increasing number of trials have shown a correlation among polyphenol consumption and a reduction in risk factors for chronic diseases, discrepancies in explaining their positive effects have been found in terms of the bioavailability. In fact, polyphenols show a low bioavailability due to several factors: interaction with the food matrix, the metabolic processes mediated by the liver (phase I and II metabolism), intestine and microbiota. On the other hand, the biological activities of phenol compounds may be mediated by their metabolites, which are produced in vivo, and recent studies have confirmed that these molecules may have antioxidant and anti-phlogistic properties. This review discusses the studies performed in vivo, which consider the polyphenol bioavailability and their different food sources. Factors influencing the biological effects of the main classes of polyphenols are also considered.